14alpha-hydroxy-11-desoxycorticosterone and 21-acylates thereof



United States Patent ldmllYDROXY-ll-DESOXYCORTICOSTERONE AND 21-ACYLATES THEREOF Herbert C. Murray, Hickory Corners, and Durcy H. Peterson','-Kalamazoo, Mich., assignors'to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application August 28, 1952, Serial No. 306,925

7 Claims. (Cl.260397;45)

may be prepared by esterification of 14a-hydroxy-ll-desoxycorticosterone. The l4a-hydroxy-1l-desoxycorticosterone of the present .invention is prepared by exposing ll-desoxycorticosterone-2l-acetate [Steiger et a1. Helv. Chim. Acta, 20, 1164 (1937)] to the oxygenating action of the fungus M ucor griseacyanus, a species of the genus Mucor of the family Mucoraceae of the order Mucorales, as described in the applications, of which this is a continuation-in-part, Serial No. 297,242, filed July 5, 1952, Serial No. 272,944, filed February 23, 1952, and issued as U. S. Patent 2,602,769, and Serial No. 180,496, filed August 19, 1950, and now abandoned.

lt is an object of the present invention to prepare 14ahydroxy-ll-desoxycorticosterone and l4a-hydroxy-l1- desoxycorticosterone-Zl-acylates. Other objects will be apparent to those skilled in-the art to which this invention pertains.

The compounds of the present invention demonstrate pronounced anaesthetic, salt retention, gluco'corticoid, hypertensive, estrogenic, testoid, folliculoid, luteoid, spermatogcnic and progesterone activities. The compounds of the present inventionalso possesses lyophobic andan increased proportion of lyophilicgroups causing-them to be valuable "interfacial tension modifying agents useful as emulsifying agents, emulsion breakers, suspending agents, and emulsion stabilizing agents. They may be usedto prepare absorption bases having improved water'absorption and emollient characteristics of utility in pharmacy and cosmetology alone, or as carriers for known medicaments. A suitable absorption base preparation may be made by melting together a mixture of 85 percent white petroleum, ten percent stearyl alcohol, and five percent oxygenated steroid, for example, 14m-hydroxy-1l-desoxycorticosterone-Zl-acetate, and cooling the mixture while stirring until it congeals. The resulting absorption base may be readily triturated with aqueous material, at room temperature, or emulsified at elevated temperature, to form a smooth and stable water-in-oil emulsion. The compounds of the present invention are also useful in the preparation of cardiac active hormones.

The compounds of the present invention can be converted to the known 5-androstene-35,l4a-diol-l7-one 3- acetate [Andre et a1. Abstracts Am. Chem. Soc., Meeting, Bufialo, 38K (1952)] by oxidizing the 14a-hydroxy-11- desoxycorticosterone-Zl-acylates with chromicv acid in acetic acidto produce 14e-hydroxyandrostendioneand reduction of the latter compound with sodium borohydride produces 5-androstene-3 3,14u-dio1-17-one. The resulting 5-androstene-3fi,l4u-diol-l7-one can be readily acetylated with acetic anhydride in pyridine to-produce 5-androstene-Bfi,l4a-diol-l7-one-3-acetate.

In the preparation of the esters of 14a-hydroxy-11- desoxycorticosterone the starting l4a-hydroxy-l l-ldesoxycorticosterone is admixed with-an acylating agentssuchvas, for example, ketene, a ketene of a-selected acid,-'anlacid, acid chloride, or acid anhydride, or other known acylating agent, usually in a solvent such as, for example, pyridine or the like, or an inert solvent, including solvents like benzene, toluene, ether, and the like, and heated at a tem* perature between about zero degrees centigrade and the boiling point of the reactionmixture, usually about room temperature, tor a periodbetween about a half hour andabout 96 hours. The time of reaction is somewhatdependent upon the temperature at which the reaction. is carried out, the acylating agent, and the ratio of reactants; The reaction mixture is quenched with ice or cold water, and the product is collected in an organic solvent whichiis thereafter washed with succesive portions of a mildly basic solution and water to obtain a solution of the product which is essentially neutral. In some instances, the product'may crystallize from the reaction mixture; in which case it may be advantageous to separate the product by'filtrationior other means, wash with water, and thereafter purify by conventional means, such as, for example; by recrystallization from a suitable solvent orchromatographicpurification, as deemed necessary.

The following examples will serve to illustratethe process and products of this invention, but thesaidin vention is not to beconsidered as limited thereto.

Examp'le 1 .14u-hydr0xy-11-desoxycorticosterone oculated with M ucor griseocyanus, ATCC 1207a and incubated for 24 hours at -a temperature of 28 degrees centig rade using a rate of aeration and stirring such that the oxygen uptake was 6.3 to 7 millimoles per hour per liter of NaSOa according to the method of Cooper, Fernstrom-and'Miller, Ind. Eng. Chem., 36,504 (.1944). To this'medium containing a 24 hour growth of Mucar griseocyanus was added 1.13 grams of ll-desoxycorticosterone-Zl-acetate in 100 milliliters of acetone to' provide a suspension of the steroid in the culture. After an additional 24 hour period ofincubation under the same conditions of temperature and aeration, the beer and mycelium were extracted. washed twice, each time with a volume of acetone approximately equal to the volume of'the mycelium and extracted .twiee, each time with a volume of methylene chloride approximately equal tothe volume of the mycelium. The acetoneand methylene chloride extractstinclutlingsolvent were added to the beer filtrate. The mixed extracts and beer filtrate were extracted successively with two one-half by volume portions of methylene chloride and then with two one-fourth by volume portions of methylene chloride. The combined methylene chloride extracts were washed with two one-tenth by volume portions of a two percent aqueous solution of sodium bicarbonate and then with two one-tenth by' volume portions of water. After drying the methylene The mycelium was filtered,-

chloride extracts with about three to five grams of anhydrous sodium sulfate per liter of solvent and filtering, the solvent was removed by distillation to yield 2.5 grams of oily crystals. The solvent-free extract was triturated exhaustively with Skellysolve B petroleum ether and then with ether, leaving 0.64 gram of brown crystals'which was dissolved in twelve milliliters of hot methanol. Filtering the mixture and cooling the filtrate to about ten degrees centigrade produced 0.2989 gram of white crystals melting at 175 to 176 degrees centigrade showing a characteristic infrared spectrum in chloroform differing from that of corticosterone, or the biconversion product of ll-desoxycorticosterone by Rhizopus arrhizus. The molecule retained the conjugated ketone, the ketal side chain, andhad one extra hydroxyl group. The infrared spectrum in Nujol mineral oil showed an additional extra hydroxyl indicating the possibility that a methanolate of 14a-hydroxy-1l-desoxycorticosterone was produced having a carbon-hydrogen analysis as follows:

Analysis.Calculated for C21H30O4: C, 72.80; H, 8.73. Found (dried at 50 degrees centigrade): C, 70.37; H, 8.70. Found (dried at 100 degrees centigrade): C, 71.14; H, 8.62.

Crystallization of the methanolate from acetone produced crystals of identical melting point and infrared spectra in chloroform but the infrared spectrum on the Nujol mull no longer difiered from that of the chloroform solution. The thus produced 14a-hydroxy-l1-desoxycorticosterone melted at 175 to 176 degrees centigrade.

Analysis-Calculated for Carl-13004: C, 72.80; H, 8.73. Found: C, 72.16; H, 8.60.

Example 2.-14a-hydr0xy-1 1 -desxycorticosterone- 21 -acetate An SI-milligram sample of l4a-hydroxy-11-desoxycor ticosterone was dissolved in two milliliters of absolute pyridine and one milliliter of acetic anhydride, chilled with ice, and diluted wth ice water. The resulting precipitate'was filtered to give" 88 milligrams of crystals which were dissolved in two milliliters of acetone. The resulting solution was concentrated and diluted with hexane to cloudiness and after two reerystallizations from acetone-hexane the compound had a melting point of 158 to 161 degrees'centigrade. The infrared spectrum verified the structure of a monoacetate and the optical rotation M1 was plus 192 degrees (0.53 in chloroform).

. Analysis.-Calculated for CzaHazOs: C, 71.10; H, 8.30. Found: C, 71.00; H, 8.71.

Example 3.14a-hydr0xy-1I-desoxycorticosterone- 21 -dz'methylacelate In the same manner as given in Example 2, using the equivalent proportion of benzoyl chloride in place of acetic anhydride produced hydroxy 11 desoxycorticosterone-21-benzoate.

Example 6.--14a-hydroxy11 -des0xyc0rtic0ster0ne- 21 -trimethylacetate In the same manner as given in Example 2, using the equivalent proportion of trimethylacetic anhydride" in place of acetic anhydride produced l4a-hydroxy-l1-desoxycorticosterone-Zl-trimethylacetate.

In a similar manner, other esters of l4a-hydroxy-lldesoxycorticosterone are prepared by reacting l4a-hydroxy-ll-desoxycorticosterone with the selected acid anhydride in pyridine or with other acylating agents and solvents as previously described in this specification. Representative esters of l4a-hydroxy-1l-desoxycorticosterone thus prepared suitably include one to eight carbon atom carboxylic acid acyloxy esters of saturated or unsaturated aliphatic or cycloaliphatic, carbocyclic, aryl, arylalkyl, alkaryl, mono-, dior poly-carboxylic acids, which form ester groups such as, for example, formyloxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoxy, phenylacetoxy, tolnoyloxy, cyclopentylformyloxy, acryloxy, cyclohexylformyloxy, fl-cyclopentylpropionyloxy, the half and diesters of malonic, maleic, succinic, glutaric, adipic acids, and the like. The acids may also contain non-interfering substituents, such as mono or poly, chloro, bromo, hydroxy, methoxy, and the like.

It is to be understood that the invention is not to be limited to the exact details or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 7 1. A compound represented by the graphical formula:

$H2OR o=0 CH3 1 i OH wherein R is selected from the radicals consisting of hydrogen and hydrocarbon-carboxylic acyl radical containing from one to eight carbon atoms, inclusively.

2. 14a-hydroxy-1l-desoxycorticosterone.

3. A 14a-hydroxy-11-desoxycorticosterone-2l-acylate ester of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusively.

4. 14a-hydr0xy-l l-desoxycorticosterone-Zl-acetate.

5. l4u-hydroxy-1bdesoxycorticosterone 2l-(,8-cyclm pentylpropionate).

6. 14a-hydroxy-ll-desoxycorticosterone-2l-benzoate.

7. 14a-hydroxy-ll-desoxycorticosterone-Zl-trimethylacetate.

No references cited. 

1. A COMPOUND REPRESENTED BY THE GRAPHIC FORMULA: 